The immature skeletal muscle has the unique capacity to attain an extraordinarily high growth rate in the perinatal period, provided the nutrient supply is optimal. This growth potential is enabled by a heightened capacity for protein synthesis and rapid satellite cell proliferation. When nutrient intake during the perinatal period is inadequate, muscle mass is markedly and permanently compromised even upon nutritional rehabilitation. This limited response is inconsistent with the enormous regenerative capacity of skeletal muscle. Studies in mice are proposed to test the hypotheses that: (i) nutritional deprivation during the suckling period inhibits myonuclear accretion, and nutritional rehabilitation after weaning cannot restore muscle mass because the mitogenic environment necessary to promote satellite cell replication is no longer present;(ii) interventions that promote myonuclear accretion can reverse the nutritionally induced deficit in muscle mass. Four studies are proposed to test these hypotheses. The specific aims of these are: (1) To determine the relative contributions of an impairment in the ability of the muscle to accelerate protein versus myonuclear accretion upon refeeding following a period of undernutrition during the suckling period. (2) To determine if the deficit in muscle mass incurred by undernutrition during the suckling period can be recuperated by the sustained expression of muscle IGF-I during nutritional rehabilitation. (3) To determine the efficacy of a voluntary resistance-endurance exercise program concurrent with nutritional rehabilitation in restoring the nutritionally-induced muscle mass deficit. (4) To compare the capacity for muscle regeneration in mice that have been nutritionally rehabilitated after being undernourished during the suckling period. Relevance: The prevalence of sarcopenia (loss of skeletal muscle with aging) is increasing both nationally and globally. Compelling epidemiological and experimental evidence have revealed that an individual's risk of developing sarcopenia and other chronic diseases of adulthood is influenced by their perinatal nutritional experiences. Although skeletal muscle is a central determinant of an individual's quality of life as they age, and is known to be vulnerable to the effects of nutrition in early life, we do not know the mechanisms responsible for this adverse programming of skeletal muscle, the exact window of development when muscle growth is vulnerable, and if there are interventions that can reverse this early programming.